Taxanes such as paclitaxel are diterpene natural product drug molecules that have been used to treat cancer in the clinic for many years. Synthetic analogs of paclitaxel such as docetaxel have been developed and also used in the clinic to treat various cancers. The taxanes act by binding to tubulin and stabilizing the mitotic spindle thereby halting mitosis and leading cells into apoptosis. However the taxanes and other drug molecules have been found to be ineffective in treating multidrug resistant cancers and cancers with mutant tubulins. Therefore a continuing need exists for compounds that are effective therapeutic agents for cancers that are multidrug resistant.
One approach in developing new anti-cancer drugs is the identification of superior analogs and derivatives of biologically active compounds. Modifications of various portions of a complex molecule may lead to new and better drugs having improved properties such as increased biological activity, effectiveness against cancer cells that have developed multi-drug resistance (MDR), fewer or less serious side effects, improved solubility characteristics, better therapeutic profile and the like.
Zamir et al, Tetrahedron Letters, 37, 6435-6438 (1996) discloses taxane analogues containing a five membered A-ring and a position 1 —C(CH3)2OH group. These analogues were abeo-taxanes lacking the four membered oxatane ring. Zamir et al, Tetrahedron Letters, 53. 15991-16008 (1997) discloses abeo-taxane analogues and also trapped intermediates containing a 5 membered A-ring and a position 1 —C(CH3)2OH group. Wahl et al, Tetrahedron, 48, 6965-6974 (1992) discloses a wide range of modified taxane analogues including one which had a 5 membered A-ring and a 1 position —C(CH3)2OH group.
U.S. Pat. No. 5,352,806 discloses 10β-substituted taxanes which may have bridges between the 7- and 9-hydroxyl groups of the formula:
wherein R11 and R12 are as defined in the patent.